This Academic Research Enhancement Award (AREA) proposal addresses the effects of prenatal exposure to delta-9-tetrahydrocannabinol (THC) on the neuroendocrine and immune systems of the developing and adult male and female offspring. Although marijuana exposure during pregnancy has been shown to produce long-lasting neuroendocrine effects in the offspring, possible effects on the immune system have not been studied. In preliminary studies, THC, the major psychoactive component of marijuana, administered to pregnant rats during the last week of gestation, has been shown to disturb the hormonal milieu of mother and fetus. Because the developing immune and neuroendocrine systems of the fetus are vulnerable to changes in the hormone environment at this time, the male and female offspring exposed to THC may have compromised immune and neuroendocrine function. Indeed, preliminary findings support this hypothesis in that thymus and spleen weights were significantly altered during development and in adult male and female offspring. Moreover, hypothalamic neurotransmitter content, prolactin levels, and copulatory behavior parameters were also affected in the offspring exposed to THC in utero. Do the changes in thymus and spleen weight reflect alterations in immune function? Are the neuroendocrine axes (hypothalamic-pituitary-adrenal and -gonadal) that directly and indirectly affect the function of the immune system compromised as a result of exposure to THC during a critical stage of CNS development? In this proposal the applicant will examine these questions by 1) measuring the effects of a wide dose range of THC (0.5-10 mg/kg) administered prenatally on immune and neuroendocrine parameters of developing and adult offspring. As only one concentration of THC (5 mg/kg) has been administered to preliminary rats thus far, testing the effects of a wider dose range will provide important dose-response data and allow optimal doses of THC to be utilized in future studies; 2) Determine the effects of prenatal THC exposure on the ability of T and B cells to respond to specific mitogens. Measuring the mitogen-induced proliferation responses of Iymphocytes obtained from the thymus and spleen of developing and adult male and female offspring will impart important information concerning basic immunocompetence; 3) Examine the histology of thymus and spleen tissues during development and in adult male and female offspring exposed to vehicle or THC in utero; 4) Determine if in utero exposure to THC alters hypothalamic-pituitary-adrenal and/or -gonadal function of the male and female offspring. Together, these results will provide new and much-needed information concerning the potential effects of in utero THC exposure on immune and neuroendocrine function which, in turn, will lead to a better understanding of maternal drug abuse and its effects on male and female offspring.